The aim of the project is to develop alternative treatment for noninfectious intraocular inflammatory diseases (uveoretinitis). During this past year we concentrated on a group of noncytotoxic immunosuppressants comprising rapamycin (RAPA), cyclosporin A (CsA), and FK506. The work specifically focused on (1) RAPA treatment of experimental autoimmune uveoretinitis (EAU) and (2) combination therapy using RAPA with dexamethasone (Dex) or CsA. The noncytotoxic immunosuppressants inhibit the immune system function mainly by preventing the proliferation of activated lymphocytes. CsA and FK506 both prevent lymphokine gene expression. RAPA exerts its action at a different level by interfering with the transduction of the proliferative signal of cellular growth factors. In our studies of the efficacy of RAPA in EAU in the Lewis rat, EAU was inhibited when RAPA treatment was instituted either on the day of immunization with S-antigen (S-Ag) or 7 days later (minimal effective dose, 0.1 mg/kg/day). The inhibition of EAU was correlated with reduced lymphocyte proliferation and antibody production to S-Ag. RAPA also was shown to prevent the adoptive transfer of EAU with a retinal antigen-specific T-cell line, indicating that it could be effective in the treatment of ongoing disease. Drug combination is commonly used as a strategy to minimize the toxicity of each drug while achieving a full therapeutic effect. Our studies of the combination of RAPA with Dex or CsA in vitro have shown a potent synergistic action of these drugs. In combination, RAPA and CsA could be reduced by 10- and 3-fold, respectively, while Dex with RAPA allowed for a 4.5-fold reduction of both.